CHASAP: Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy

Sponsor

Centre Hospitalier Intercommunal Creteil (Other)

Overall Status

Recruiting

CT.gov ID

NCT04356326

Collaborator

(none)

500

Enrollment

Locations

Arms

91.5

Anticipated Duration (Months)

29.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A randomized clinical trial to assess the efficiency of acetylsalicylic acid (aspirin) 150 mg/day started before 20 weeks of gestation in the prevention on maternal and fœtal complications in pregnant women with chronic hypertension.

Condition or Disease	Intervention/Treatment	Phase
Chronic Hypertension Complicating Pregnancy Pre-Eclampsia Intrauterine Growth Restriction Aspirin Perinatal Death Placental Abruption	Drug: Aspirin 150 mg Drug: Placebo	Phase 3

Detailed Description

Chronic hypertension affects 1 to 5% of women of childbearing age. According to the literature, about 45% of pregnant women with chronic hypertension will develop complications such as superimposed preeclampsia (PE), placental abruption, Intra Uterine Growth Restriction (IUGR), perinatal death, maternal death, or preterm delivery. To date, there is no curative treatment of vascular complications of chronic hypertension during pregnancy. The only effective treatment, once the complications are established, is usually stopping the pregnancy and delivering the placenta. The preventive treatment of these complications is therefore an important axis in the improvement of maternal and perinatal health.

Due to the very high risk of superimposed PE in chronic hypertensive patients and despite the lack of objective evidence of the effectiveness of low-dose aspirin in the prevention of superimposed PE in this population, the NICE (National Institute for Health and Care Excellence), associated with the Royal College of Gynecology-Obstetrics, recommends since 2010-2011 the use of low-dose aspirin in the prevention of this complication in chronic hypertensive pregnant women; then it was followed by the "U.S. Preventive Services Task Force (USPTF)" in 2014. Recently, the American College of Obstetrics and Gynecology (ACOG) adopted the suggestions of the USPTF and issued the same recommendations in 2018. The French college of obstetric (CNGOF: National College of French Gynecologists and Obstetricians), however, does not recommend the use of low-dose aspirin in pregnant chronic hypertensive women because of insufficient data.

Indeed, although the efficacy of low-dose aspirin is assumed in patients with previous PE, few studies have evaluated its efficacy in patients with chronic hypertension. Moreover, most of the controlled prospective studies using very low doses of aspirin (less than 100 mg) and starting after 20 weeks of gestation do not seem conclusive. For these reasons, the investigators propose to conduct a prospective randomized double-blind placebo-controlled trial to analyze the effectiveness of aspirin dosed at 150 mg and introduced before 20 weeks of gestation in women with chronic hypertension.

The primary endpoint is a maternal and perinatal composite morbidity and mortality including superimposed PE, intrauterine growth restriction, preterm delivery < 37 weeks of gestation, placental abruption, perinatal death, or maternal death.

The definition of superimposed PE in our study is the appearance of significant proteinuria in a chronic hypertensive pregnant woman.

In a secondary analyze, the statistician will use the new definition of superimposed PE that does not require the mandatory presence of proteinuria but the association of chronic hypertension and the appearance of neurological signs (eclampsia, persistent headache, visual disturbances, severe nausea or vomiting), pulmonary edema, persistent epigastric pain, thrombocytopenia <100000 platelets/µL, liver enzymes at 2 times normal, renal insufficiency ( serum creatinine ≥ 97 μmol/L or 1.1 mg/dL,) or a doubling of serum creatinine in the absence of chronic renal disease or significant proteinuria after 20 weeks of gestation or postpartum.

Significant proteinuria is defined as greater than 300 mg/24 hours or when the ratio proteinuria/ creatininuria is ≥ 30 mg/mmol (ratio to 0.3 if all are in mg/dL), in a non-proteinuric women with no urinary tract infection.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective multicentric randomized double-blind superiority trial, placebo-controlled, on two parallel armsProspective multicentric randomized double-blind superiority trial, placebo-controlled, on two parallel arms

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

The treatment will be administered double blind. Pouches or tablets and caskets will be indistinguishable, prepared in advance and made available to pharmacies in participating hospitals by the sponsor. The treatment boxes are given as the monthly visits to the patient, a reassignment box will be required on the server at each visit to obtain a new cabinet number. The cabinet number (detachable label) used at each visit will be reported in the patient's file.

Primary Purpose:

Treatment

Official Title:

Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy, a Multicenter Prospective Randomized Double-blind Placebo-controlled Trial.

Actual Study Start Date :

Feb 15, 2021

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Oct 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aspirin 150 mg Aspirin 150 mg / day (acetylsalicylic acid) once daily in the evening	Drug: Aspirin 150 mg Treatment assigned by randomization will be prescribed immediately and continued throughout pregnancy up to 35 weeks + 6 days for both groups. The active or placebo will be dispensed by the centre's pharmacy. Treatment will be taken in the evening. A daily log is given to patients and must be completed every day. Other Names: Active arm
Placebo Comparator: Placebo Placebo taken in the evening	Drug: Placebo Treatment assigned by randomization will be prescribed immediately and continued throughout pregnancy up to 35 weeks + 6 days for both groups. The active or placebo will be dispensed by the centre's pharmacy. Treatment will be taken in the evening. A daily log is given to patients and must be completed every day. Other Names: comparator arm

Arm

Intervention/Treatment

Experimental: Aspirin 150 mg

Aspirin 150 mg / day (acetylsalicylic acid) once daily in the evening

Drug: Aspirin 150 mg

Treatment assigned by randomization will be prescribed immediately and continued throughout pregnancy up to 35 weeks + 6 days for both groups. The active or placebo will be dispensed by the centre's pharmacy. Treatment will be taken in the evening. A daily log is given to patients and must be completed every day.

Other Names:

Active arm

Placebo Comparator: Placebo

Placebo taken in the evening

Drug: Placebo

Other Names:

comparator arm

Outcome Measures

Primary Outcome Measures

Composite morbidity-mortality criterion including preeclampsia, intra-uterine growth retardation <10th percentile, placental abruption, Preterm birth < 37 weeks of gestation, Perinatal death, Maternal death [9 months]
A composite morbidity-mortality criterion that includes the occurrence during pregnancy or postpartum of at least one of the following events: preeclampsia, IUGR <10th percentile, placental abruption, Preterm birth < 37 weeks of gestation, Perinatal death (death from 22 weeks of gestation until 28 days after birth), Maternal death

Secondary Outcome Measures

IUGR (< 10th percentile of birth weight) [9 months]
Rate of IUGR (< 10th percentile of birth weight)
Placental abruption [9 months]
Rate of placental abruption
Preterm birth < 37 weeks of gestation [9 months]
Rate of severe preterm delivery (< 37 weeks of gestation)
Maternal death [9 months]
Rate of severe maternal death
Severe pre-eclampsia [9 months]
Rate of severe pre-eclampsia. Concerning the rate of superimposed PE, it will be analyze according the two definition specified in the rational
Intrauterine growth restriction (IUGR) [9 months]
Rate of severe IUGR (< 5th percentile of birth weight)
Preterm delivery [8 months]
Rate of severe preterm delivery (< 34 weeks of gestation)
Fetal loss [5 months]
Rate of fetal loss (fetal loss between 10 and 21 weeks of gestation)
Fetal death [5 months]
Rate of fetal death (fetal death from 22 weeks of gestation until delivery)
Neonatal death [9 months]
Rate of neonatal death (death from birth until 28 days)
Neonatal morbidity [9 months]
Neonatal morbidity (stay in a neonatal intensive care unit, assisted ventilation > 24 hours, hyaline membrane disease, intraventricular hemorrhages stage III or IV)
Toxicity of aspirin [8 months]
Potential toxicity of the treatment: major maternal bleeding event (active externalized, intracranial, intra-ocular, retroperitoneal, articular), or minor,
Adherence [8 months]
Adherence of treatment (diary) and its relationship with the efficacy of the preventive effect on primary outcome,
Biological response to the treatment [4 months]
Response to the treatment by a urine thromboxane assay
Angiogenic profile [9 months]
Circulating and urinary angiogenic profile associated with maternal and fetal clinical data: sFLT1 ( Soluble fms-like tyrosine kinase-1)(serum and urine), PlGF ( Placental Growth Factor)(serum and urine)
Child development [2 years]
Child psychomotor development and health problems at 2 years of age
Child development [4 years]
Child psychomotor development and health problems at 4 years of age
Subgroups analysis [9 months]
Rate of the composite morbidity-mortality criterion in 2 subgroups: treatment started before or after 15 SA

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Pregnant patient between 10 and 19 weeks of gestation + 6 days
Chronic hypertension, whether treated or not, know before pregnancy or diagnosed before randomization
Singleton pregnancy
Signed the written informed consent
Affiliation to social security

Exclusion Criteria:

---Medical history requiring anticoagulation (antiphospholipid syndrome, deep vein thromboembolic disease, pulmonary embolism, atherothrombosis, patient with mechanical heart valves),
Patient receiving aspirin for another indication outside pregnancy,
Patient with significant proteinuria (> 300mg/24 hours or a proteinuria/creatininuria ratio ≥ 30mg/mmol),
Active bleeding,
History of severe PE with delivery < 34 weeks of gestation,
Hypersensitivity to salicylates such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs),
Platelet count lower than 100,000 cells/microliter (dosage less than 6 months old),
Hemostasis disorders, including hemophilia (with thrombocytopenia)
Any constitutional or acquired hemorrhagic disease, (including digestive hemorrhages, history of hemorrhagic stroke and thrombocytopenia
Human immunodeficiency virus, or hepatitis B virus, or hepatitis C virus positive serum,
Patient included in an another interventional study,
Age <18 years old,
Women under the protection of justice,
Patients with psychiatric follow-up, poor understanding of French or cognitive problems,
Duodenal ulcer,
Severe renal impairment,
Severe hepatic insufficiency,
Severe cardiac impairment,
Gout,
Patients with known glucose-6-phosphate dehydrogenase deficiency,

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU Bordeaux	Bordeaux	France
2	CHU Caen	Caen	France	14000
3	CHU Antoine Béclère, AP-HP	Clamart	France
4	Hôpital Louis Mourier, AP-HP	Colombes	France
5	Centre Hospitalier Intercommunal de Créteil	Créteil	France	94000
6	CHU Dijon	Dijon	France
7	CHU Bicêtre, AP-HP	Le Kremlin-Bicêtre	France
8	CHU Lyon	Lyon	France
9	Hôpital St Joseph	Marseille	France
10	CHRU Nancy	Nancy	France
11	CHU Nantes	Nantes	France
12	CHU Cochin- Port Royal, AP-HP	Paris	France
13	CHU Robert Débré, AP-HP	Paris	France
14	Hôpital Trousseau, AP-HP	Paris	France
15	CH Poissy	Poissy	France
16	CHU St Etienne	Saint-Étienne	France
17	CHU Tours	Tours	France